IN-VITRO INTERACTION OF LIPOSOMAL VALINOMYCIN AND PLATINUM ANALOGS - CYTOTOXIC AND CYTOKINETIC EFFECTS

Cisplatin is the most active agent in the chemotherapy of ovarian canc er and this activity can be enhanced by liposomal valinomycin (MLV-VM) in vitro. To test whether MLV-VM is capable of augmenting the cytotox ic and cytokinetic effects of other platinum analogs, drug combination s of MLV-VM and platinum drugs were tested against two human ovarian c ancer cell lines (OVCAR-3 and CaOV-3) and on Chinese hamster ovary (CH O) cells in vitro. MLV-VM enhanced the sensitivity to cisplatin, ormap latin and carboplatin on human ovarian carcinoma cells that show vario us degrees of drug sensitivity. This interaction was shown to be truly synergistic by median-effect analysis up to 90% cell kill. The combin ation index at 50% cell kill (Cl50) was also used to quantitate the ex tent of drug synergy. In the OVCAR-3 cell line, for example, the Cl50s were 0.62, 0.85 and 0.8 for cisplatin, ormaplatin and carboplatin, re spectively. DNA histograms obtained by flow cytometry showed that CHO cells treated with cisplatin alone accumulated in the S-G2 segment, wi th a partial G2 block. The addition of 2 muM VM with cisplatin, signif icantly enhanced the accumulation of cells at the G2/M phase. Our resu lts further demonstrate that in vitro treatment with VM, cisplatin and /or combination is associated with an increase in protein kinase C (PK C) activity. These findings suggest that accumulation of cells at G2/M phases and modulation of PKC activity could be among the basis for th e cytotoxic synergism observed between cisplatin and VM.